Process for making metabolites of lycopene

ABSTRACT

The invention is concerned with a multi-stage process for making an oxidative metabolite of the carotenoid lycopene, 2,6-cyclolycopene-1,5-diol having the formula ##STR1## In this process α-terpinyl acetate is oxidatively dihydroxylated to a cyclohexanediol (IV), the cyclohexanediol (IV) is oxidatively cleaved to a ketoaldehyde (V), the ketoaldehyde (V) is subjected to an intramolecular aldol condensation to give a cyclopentanol (VI), the cyclopentanol (VI) is silylated to its silylated derivative formylcylopentane (VII), the formylcyclopentane (VII) is subjected to a C 3  -chain lengthening with acetone and simultaneously to a saponification for the cleavage of the acetyl group to give a cyclopentylbutenone (VIII), the cyclopentylbutenone (VIII) is reacted with vinyl magnesium bromide to give a pentadienol (IX), the pentadienol (IX) is converted with deprotection of the silylated hydroxy group into a phosphonium salt (X), this salt is subjected to a Wittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial to give a tridecahexaenal (XII) and the tridecahexaenal (XII) is subjected to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt to give the desired 2,6-cyclolycopene-1,5-diol (II). A variant of this process, also in accordance with the invention, comprises converting the cyclopentylbutenone (VIII) into the phosphonium salt (X) via two alternative intermediates, namely a pentadienoic acid ester (XIV) and a different pentadienol (XV), into the same phosphonium salt (X). Moreover, the invention is concerned with the novel intermediates (V), (VI), (VII), (VIII), (IX), (X), (XII), (XIV) as well as (XV) and the individual process steps which lead to these novel intermediates. 2,6-cyclolycopene-1,5-diol is useful in the prevention of cancer growth in human cells.

FIELD OF THE INVENTION

The present invention is concerned with a multi-stage process for themanufacture of an oxidative metabolite of the carotenoid lycopene aswell a novel intermediates produced in the manufacturing process.

BACKGROUND OF THE INVENTION

As is known, carotenoids, inter alia, lycopene, play an important rolein the chemoprevention (prophylaxis) of cancer [see, for example, J. S.Bertram, Pure & Appl. Chem. 66, 1025-1032 (1994) and the literaturereferences mentioned therein; N.I. Krinsky, Nat. Antioxid. Health Dis.1994, 239-261; J. S. Bertram, Oxid. Stress Aging 1995, 221-235; as wellas T. Narisawa et al., Cancer Lett. 107(1), 137-142 (1996)], and theiruse in clinical research is well established. [A. Bendich, Pure & Appl.Chem. 66, 1017-1024 (1994) and the literature references mentionedtherein]. Levy et al. have demonstrated the preventative activity oflycopene, having the formula ##STR2## against the growth of humanendometrial, breast and lung cancer cells [Nutr. Cancer, 24, 257-266(1995)]. E. Giovannucci et al. disclose in J. Natl. Cancer Inst. 87,1767-1776 (1995) that a diet rich in lycopene reduces the risk ofprostate cancer.

The red carotenoid lycopene is present in tomatoes and among otherfruits. A finding that, with respect to the activity against cancer,cooked tomatoes are substantially more active than raw could be due tothe fact that after boiling the lycopene has an improved bioavailabilty;on the other hand, the biologically active compound could be anoxidation product or a metabolite of lycopene. In recent investigationson the carotenoid content of human blood plasma, new lycopenemetabolites have been identified, namely 2,6-cyclolycopene-1,5-diol and5,6-dihydroxy-5,6-dihydrolycopene [F. Khachik et al., J. Cell Biochem.1995 (Suppl. 22), 236-246 and 11th International Symposium onCarotenoids, Leiden 1996, O.P.1.3; as well as F. Khachik, Book ofAbstracts, 213th ACS Nat. Meeting, San Francisco, April 13-14, 1997].The first-mentioned known metabolite, having the formula ##STR3## showsactivity in and is useful in the prevention of cancer growth in humanand mouse cells.

Two syntheses of oxidative metabolites of lycopene have been reported,namely in Biosci. Biotechn. Biochem. 59, 2153-2155 (1995; Y. Lu et al.)and in the aforementioned 11th Int. Symp. on Carotenoids, Leiden 1996(O.P.3.5; F. Khachik et al.). These are partial syntheses, each of whichstarts from lycopene itself. It has now been found that2,6-cyclolycopene-1,5-diol (II) can be made by a multi-stage process,namely starting from the readily available α-terpinyl acetate. Thisprocess is the first total synthesis of an oxidatively producedmetabolite of lycopene.

SUMMARY OF THE INVENTION

The invention is accordingly concerned with a process for making thecompound of formula II, which comprises the steps of (a) oxidativelydihydroxylating α-terpinyl acetate having the formula ##STR4## to form4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having theformula ##STR5## (cyclohexanediol (IV)), (b) oxidatively cleaving thecyclohexanediol (IV) to form 3-(1-acetoxy-l-methylethyl)-6-oxo-heptanalhaving the formula ##STR6## (ketoaldehyde (V)), (c) subjecting theketoaldehyde (V) to an intramolecular aldol condensation to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having theformula ##STR7## (cyclopentanol (VI)), (d) silylating the cyclopentanol(VI) to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentanehaving the formula ##STR8## (formylcyclopentane (VII)), (e) subjectingthe formylcyclopentane (VII) to a C₃ -chain lengthening with acetone andsimultaneously to a saponification for the cleavage of the acetyl groupto form4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-onehaving the formula ##STR9## (cyclopentylbutenone (VIII)), (f) reactingthe cyclopentylbutenone (VIII) with vinylmagnesium bromide to form5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-olhaving the formula ##STR10## (pentadienol (IX)), (g) converting thepentadienol (IX) with deprotection of the silylated hydroxy group into a(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt having the formula ##STR11##

wherein Ph is phenyl and X¹⁻⁻ is halide or hydrogen sulphate,(phosphonium salt (X)), (h) subjecting the phosphonium salt (X) to aWittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial having theformula ##STR12## (C₁₀ -dial (XI)) to form2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenalhaving the formula ##STR13## (tridecahexaenal (XII)), and (i) subjectingthe tridecahexaenal (XII) to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt havingthe formula ##STR14##

wherein Ph is phenyl and X² - is halide or hydrogen sulphate,(phosphonium salt (XIII)) to form the compound of formula II.

The present invention is concerned with novel intermediates used in theaforementioned process and in particular those intermediates of formulaeV, VI, VII, VIII, IX, X and XII. In addition, the present invention isalso concerned with the individual process steps IV→V, V→VI, VI→VII,VII→VIII, VIII→IX, IX→X, X+XI→XII and XII+XIII→II, that is, theone-stage processes described above for the production of the novelintermediates and the known final product II. The compounds of formulaeIII, IV, XI and XIII are known: see, inter alia, T. Hirata et al., Chem.Lett. 1982, 671-674 (cyclohexanediol (IV)) as well as U.S. Pat. No.5,166,445 and Helv. Chim. Acta 75, 1848 -1865 (1992) (phosphonium salt(XIII)).

DETAILED DESCRIPTION OF THE INVENTION

The invention is accordingly concerned with a process making thecompound of formula II, which comprises the steps of (a) oxidativelydihydroxylating α-terpinyl acetate having the formula ##STR15## to form4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having theformula ##STR16## (cyclohexanediol (IV)), (b) oxidatively cleaving thecyclohexanediol (IV) to form 3-(1-acetoxy-l-methylethyl)-6-oxo-heptanalhaving the formula ##STR17## (ketoaldehyde (V)), (c) subjecting theketoaldehyde (V) to an intramolecular aldol condensation to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having theformula ##STR18## (cyclopentanol (VI)), (d) silylating the cyclopentanol(VI) to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentanehaving the formula ##STR19## (formylcyclopentane (VII)), (e) subjectingthe formylcyclopentane (VII) to a C₃ -chain lengthening with acetone andsimultaneously to a saponification for the cleavage of the acetyl groupto form4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-onehaving the formula ##STR20## (cyclopentylbutenone (VIII)), (f) reactingthe cyclopentylbutenone (VIII) with vinylmagnesium bromide to form5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-olhaving the formula ##STR21## (pentadienol (IX)), (g) converting thepentadienol (IX) with deprotection of the silylated hydroxy group into a(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt having the formula ##STR22##

wherein Ph is phenyl and X¹⁻⁻ is halide or hydrogen sulphate,(phosphonium salt (X)), (h) subjecting the phosphonium salt (X) to aWittig reaction with 2,7-dimethyl-2,4,6-octatriene-1,8-dial having theformula ##STR23## (C₁₀ -dial (XI)) to form2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenalhaving the formula ##STR24## (tridecahexaenal (XII)), and (i) subjectingthe tridecahexaenal (XII) to a Wittig reaction with a(3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salthaving the formula ##STR25##

wherein Ph is phenyl and X²⁻⁻ is halide or hydrogen sulphate,(phosphonium salt (XIII)) to form the compound of formula II.

The present invention is concerned with novel intermediates used in theaforementioned process and in particular those intermediates of formulaeV, VI, VII, VIII, IX, X and XII. In addition, the present invention isalso concerned with the individual process steps IV→V, V→VI, VI→VII,VII→VIII, VIII→IX, IX→X, X+XI→XII and XII+XIII→II, that is, theone-stage processes described above for the production of the novelintermediates and the known final product II. The compounds of formulaeIII, IV, XI and XIII are known: see, inter alia, T. Hirata et al., Chem.Lett. 1982, 671-674 (cyclohexanediol (IV)) as well as U.S. Pat. No.5,166,445 and Helv. Chim. Acta 75, 1848 -1865 (1992) (phosphonium salt(XIII)).

A variant of the process in accordance with the present inventiondescribed above comprises converting the cyclopentylbutenone (VIII),made by steps (a) through (e) as set forth above, into the phosphoniumsalt (X) not via the pentadianol (IX), but converting it into the samephosphonium salt (X) via two alternative intermediates; this variantinvolves three process steps and comprises the steps of subjecting thecyclopentylbutenone (VIII) to a Horner-Emmons olefination with atrialkyl phosphonoacetate in the presence of a base to form thecorresponding alkyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methylpenta-2,4-dienoatehaving the formula ##STR26##

wherein Alkyl is C₁₋₆ -alkyl, (pentadienoic acid ester (XIV)), reducingthe pentadienoic acid ester (XIV) with deprotection of the silylatedhydroxy group to form5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dien-1-olhaving the formula ##STR27## (pentadienol (XV)), and converting thepentadienol (XV) into the(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt of formula X given above (phosphonium salt (X)). The remainder ofthe multi-stage process for making 2,6-cyclolycopene-1,5-diol, that is,process steps X+XI→XII and XII+XIII→II, is effected as defined anddescribed above. The thus-modified process for making the lycopenemetabolite 2,6-cyclolycopene-1,5-diol of formula II starting froma-terpinyl acetate represents a further aspect of the present invention,as do the novel intermediates of formulae XIV and XV produced in thevariant as well as the individual processes steps VIII→XIV, XIV→XV andXV→X, that is, the one-stage processes defined above for the productionof the novel intermediates.

As used herein, halide refers to fluoride, chloride, bromide, andiodide. Chloride and bromide are preferred with bromide being especiallypreferred.

As used herein, C₁₋₆ -alkyl includes, for example, straight and branchedchains such as, for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert. butyl, pentyl, isopentyl, neopentyl, hexyl,isohexyl, etc.

The oxidative dihydroxylation of α-terpinyl acetate (III) to thecyclohexanediol (IV) is conveniently carried out using the oxidizingagent potassium permanganate in a liquid reaction medium at relativelylow temperatures (for example, from about 0° C. to about 40° C.). As thesolvent for the a-terpinyl acetate (III) there comes into considerationespecially a polar organic solvent, such as an aliphatic or cyclicether, for example, tetrahydrofuran, or a lower (especially C₁₋₆)alkanol, for example, ethanol. The potassium permanganate, in turn, isconveniently dissolved in water, suitably at a concentration in therange of about 2 to about 7% (wt./vol.) and is added slowly in theaqueous solution to the solution of the a-terpinyl acetate. For reasonsof safety--and since the reaction generally proceeds well under theseconditions--the addition is effected at relatively low temperatures,that is, conveniently in the temperature range of about 0° C. to about40° C.; because of the danger of an over-oxidation the temperatureshould be held in the lower part of this range. Conveniently, about 0.8to about 1.0 equivalent (eq.) of potassium permanganate is used based onthe amount of educt. Moreover, during the addition it is advantageous tostir the reaction mixture vigorously and it is also suitably stirredfurther after completion of the addition. In this manner the reactionhas normally finished within a maximum of about two hours, with asuspension then being present and the desired cyclohexanediol (IV) beingin solution. In order to isolate this product, the suspension isfiltered, the filtrate is extracted with a suitable, water-immiscibleorganic solvent, such as a lower halogenated hydrocarbon, for example,methylene chloride or chloroform, an aliphatic ether, for example,diethyl ether or tert.butyl methyl ether, or a lower aliphatic ester,for example, ethyl acetate, and the organic extraction phase is dried,for example, with anhydrous sodium sulphate or magnesium sulphate, andthen evaporated under reduced pressure. If desired, the solid residuecan be purified in the usual manner, for example, by recrystallizationor column chromatography.

Instead of an aqueous solution of potassium permanganate, this oxidizingagent can be used in another form in the oxidative dihydroxylation; forthis there come into consideration, inter alia, potassium permanganatein alkaline solution, especially with aqueous alkali hydroxide solution,for example, aqueous sodium hydroxide or potassium hydroxide solution,and potassium permanganate together with magnesium sulphate inethanolic-aqueous solution. In both cases the reaction is convenientlyeffected at low temperatures, for example, in the range of the about 0°C. to about 5° C., whereby in other respects the reaction procedure canbe effected in a manner known to those of ordinary skill in the art (seeOrganikum, page 261, and W. T. Weber et al., Tetr. Lett. 1972, 4907 etseq.). Oxidizing agents other than potassium permanganate come intoconsideration, especially osmium tetroxide/hydrogen peroxide. In thiscase, typically a 6-7% solution of hydrogen peroxide in methanol,tert.butanol, acetone or glacial acetic acid and an about 0.5% solutionof osmium tetroxide in the same solvent are added to the a-terpinylacetate (III) and the reaction mixture is stirred for several days. Forfurther details reference is made, for example, to N. A. Milas et al.,J.A.C.S. 58, 1302 et seq. (1936).

The conversion of the cyclohexanediol (IV) into the ketoaldehyde (V) isa glycol cleavage as is described, for example, in Tetr. Lett. 28, 2863et seq. (1987). In the present case IV→V the glycol cleavage isconveniently effected in an aprotic polar or apolar, or even in a proticpolar, organic solvent at low to moderate temperatures and using lead(IV) acetate [Pb(OCOCH₃)₄ ] as the oxidizing agent. Preferred solventsfor this purpose are lower halogenated aliphatic hydrocarbons, forexample, methylene chloride; aromatic hydrocarbons, for example, benzeneor toluene; or lower aliphatic carboxylic acids, for example, aceticacid. The reaction is suitably effected in the temperature range ofabout -20° C. to about 50° C., preferably at about 0° C. The amount oflead (IV) acetate conveniently lies between about 1.0 and about 1.5equivalents based on the amount of educt. If desired, this agent can beadded directly, that is, without dilution, to a solution of thecyclohexanediol (IV) in the chosen solvent, or the two reactants can bedissolved or suspended in the solvent, preferably while maintaining alow temperature, especially one which lies below 5° C., and in each casewith the exclusion of moisture as far as possible. In order toneutralize the acetic acid which almost inevitably accompanies the leadacetate, the solution or suspension of the cyclohexanediol (IV) isadvantageously treated prior to the addition of the lead (IV) acetatewith anhydrous sodium carbonate or with another, rather weak, inorganicbase; mortared or finely crystalline, anhydrous sodium carbonate ispreferably used for this purpose. Moreover, it is advisable to stir thereaction mixture. In this manner the reaction has normally finishedwithin about two hours.

For the working up of the mixture obtained after the reaction, water issuitable added to this mixture and thereby its temperature is left torise to room temperature. After filtering off residual solidconstituents and separating the organic phase containing the product,product remaining in the aqueous phase can be obtained, if desired, byextraction with further organic solvent, for example, methylenechloride. A conventional treatment of the (entire) organic phase (dryingover for example, anhydrous sodium sulphate or magnesium sulphate,evaporation and, if desired, purification by column chromatography)yields the desired ketoaldehyde (V).

The next process step is the intramolecular aldol condensation of theketoaldehyde (V) to the cyclopentanol (VI). This condensation isconveniently carried out by reacting the ketoaldehyde (V) in an organicsolvent or even in water at temperatures in the range of about 0° C. tothe reflux temperature of the reaction mixture, preferably attemperatures between room temperature and about 50° C., and in thepresence of a base and also an organic acid. Suitable organic solventsare primarily lower aliphatic and cyclic ethers, for example, diethylether, tert.butyl methyl ether or tetrahydrofuran; lower aliphaticketones, for example, acetone; as well as aromatic hydrocarbons, forexample, benzene and toluene. Suitable bases are generally amines, suchas, for example, dialkylamines and trialkylamines, andnitrogen-containing heterocyclic compounds, for example, piperidine andpyrrolidine. Acids which come into consideration are, inter alia, loweraliphatic carboxylic acids, for example, acetic acid, and sulphonicacids, for example, p-toluenesulphonic acid. Both the base and thecarboxylic acid can be used in a catalytic amount (up to about 0.02molar) to about an equimolar amount based on the amount of educt. Thecondensation has normally finished within a maximum of 100 hours, itbeing observed that an equilibrium with a product:educt ratio of about1:1 is achieved at the latest after about 24 hours.

In the case of this intramolecular aldol condensation, the thus-producedcyclopentanol (VI) can be isolated from the reaction mixture and, ifdesired, purified in a manner known to those of ordinary skill in theart, especially by washing with aqueous basic and/or mineral acidicsolution, for example, aqueous sodium carbonate solution, hydrochloricacid solution and/or sodium chloride solution, extraction with asuitable organic solvent, for example with an ether, for example,tert.butyl methyl ether, separation and drying of the organic phase,evaporation of this phase and, if desired, recrystallization and/orpurification by column chromatography of the solid residue.

Silylations for the protection of a hydroxyl group are especiallyfamiliar reaction steps, inter alia, in the carotenoid field--as in thesilylation of the cyclopentanol (VI) to the formylcyclopentane (VII) inthe present multi-stage manufacturing process--in relation to whichnumerous publications exist [see, for example, F. Kienzle and R. E.Minder, Helv. Chim. Acta 61 242 (1978), A. Haag and C. H. Eugster, ibid.65, 1795 (1982), as well as D. J. Buschor and C. H. Eugster, ibid. 73,1002 (1990)]. Not only the trimethylsilyl group, but also otherprotecting groups are conceivable, provided that they are stable towardsenolates and Grignard reagents and are simultaneously acid-stable. Othertrialkylsilyl, methoxymethyl, methoxyethoxymethyl and tetrahydropyranylprotecting groups belong to them.

In the present case, it has been found to be convenient to carry out thesilylation (with a trimethylsilyl protecting group) usingtrimethylchlorosilane as the silylating agent and an aprotic polarorganic solvent. Moreover, a base is used as is usual. Suitable solventsare especially lower, halogenated aliphatic hydrocarbons, for example,methylene chloride; nitrogen-containing heterocyclic compounds, forexample, pyridine; lower aliphatic and cyclic ethers, for example,diethyl ether or tetrahydrofuran; lower aliphatic amines, for example,triethylamine; and lower aliphatic amides, for example,dimethylformamide. Suitable bases are, inter alia, lower aliphaticamines, for example, triethylamine; aromatic amines, for example,dimethylaniline; and nitrogen-containing, optionally aminatedheterocyclic compounds, for example, imidazole and4-dimethylaminopyridine. As will be evident, the amines can serve notonly as solvents, but also as bases. There are conveniently used about 2to about 4 eq. of trimethylchlorosilane and from about 2 to about 5 eq.of base relative to the amount of educt (based on 1 equivalent).

In practice, the silylation is effected by adding to a solution of thecyclopentanol (VI) and the base in the solvent the silylating agentdissolved in the same solvent, and at temperatures in the range of about-10° C. to room temperature (about 25° C.). Moreover, the addition isconveniently effected under an inert protective gas, for example,nitrogen, in order to exclude moisture as far as possible, and withstirring. Under the above conditions the silylation has normallyfinished within about 24 hours. The working up of the mixture obtainedafter the reaction can be effected in a conventional manner, forexample, by filtering off the solid constituents, evaporating thefiltrate and purifying the solid residue, for example byrecrystallization and/or column chromatography, in order to obtainedmore or less pure formylcyclopentane (VII).

The next process step, that is, the C₃ -chain lengthening with acetoneand simultaneous saponification of the formylcyclopentane (VII) to thecyclopentylbutenone (VIII), is conveniently carried out by firstlyfreshly producing a lithium dialkylamide (as the base) from alithiumalkyl, for example, n-butyllithium, and a secondary amine,especially a di(C-₁₋₆ -alkyl)amine, for example, diisopropylamine, andreacting with acetone in a suitable organic solvent, especially anaprotic polar solvent, to give the acetone enolate; then the enolate isreacted with the formylcyclopentane (VII). A suitable organic solventfor the "in situ" lithium dialkylamide production is generally anaprotic solvent, such as a lower aliphatic or cyclic ether, for example,diethyl ether or tetrahydrofuran, or an aromatic hydrocarbon, forexample, toluene. This production is, moreover, conveniently effected atrelatively low temperatures, especially in the range of about -10° C. toabout +10° C., preferably at about 0° C., under an inert protective gas,for example, nitrogen, and while stirring. The lithiumalkyl and thesecondary amine are suitably used in about equimolar amounts. After asufficient reaction period, which is normally up to about one hour, themixture is conveniently cooled to about -70° C. and subsequently theacetone is added in the same solvent. Conveniently, a clear excess ofthe lithium dialkylamide base, especially about 1.1 to about 2equivalents, is used relative to the acetone (I eq.) in order tosuppress the self-condensation of the acetone as far as possible. Aftera brief period of stirring at the low temperature the formylcyclopentane(VII) is added, conveniently in a somewhat lower molar amount than theamount of acetone. While warming the reaction mixture to about -20° C.to about 0° C. the acetone reacts with the formylcyclopentane (VII), andrelatively rapidly in the mentioned temperature range. For the isolationand purification of the thus-produced cyclopentylbutenone (VIII), themixture can be treated, for example, with saturated aqueous ammoniumchloride solution, the organic phase separated and washed with waterand/or saturated aqueous sodium chloride solution, dried over a dryingagent, such as, for example anhydrous sodium sulphate or magnesiumsulphate and the organic phase finally evaporated; if desired furtherpurification of the residue obtained can be undertaken for example byrecrystallization and/or column chromatography.

The subsequent stage of the process is a Grignard reaction. Thecyclopentylbutenone (VIII) and the vinylmagnesium bromide areconveniently reacted with one another in an aprotic, polar, organicsolvent, such as a lower aliphatic or cyclic ether, for example, diethylether or dimethoxyethane or, respectively, tetrahydrofuran,tetrahydropyran or dioxan, or an amide, for example, hexamethylphosphortriamide, and in a temperature range of about -50° C. to about0° C., preferably of about -40° C. to about -20° C. Conveniently, about2 to 4 equivalents of vinylmagnesium bromide are used per equivalent ofcyclopentylbutanone (VIII). The addition of an aliphatic amine, forexample, triethylamine, serves to increase the activity. The isolationand purification of the thus-obtained pentadienol (IX) can be carriedout analogously to the procedure described in connection with theforegoing process step VII→VIII.

As an additional embodiment in the process in accordance with theinvention, the free tertiary hydroxyl group of the cyclopentylbutenone(VIII) can be protected immediately prior to process step VIII→VII,conveniently by trimethylsilylation analogously to process step VI→VII;after the correspondingly modified process step VIII→IX the silylatedhydroxyl group can be deprotected in a conventional manner, which againyields the pentadienol (IX).

The subsequent phosphonium salt formation IX→X is conveniently carriedout by stirring a solution of the pentadienol (IX) and atriphenylphosphonium halide or triphenylphosphonium hydrogen sulphate ina polar organic solvent for several hours. Lower aliphatic alcohols, forexample, methanol and ethanol; and lower halogenated aliphatichydrocarbons, for example, methylene chloride and chloroform, areespecially suitable as such solvents. Suitable, between about 1 andabout 1.2 equivalents or triphenylphosphonium halide or hydrogensulphate are used per equivalent of pentadienol (IX). Thistriphenylphosphonium salt is preferably a halide, especially thechloride or bromide, with triphenylphosphonium bromide being particularpreferred. The reaction is conveniently carried out in the temperaturerange of about 0° C. to about 50° C., preferably at room temperature,and as a rule takes from about 12 to about 72 hours. The isolationand--where desired--purification of the thus-obtained phosphonium salt(X) can be carried out according to methods known to those of ordinaryskill in the art.

The penultimate process stage and the final process stage of themulti-stage manufacturing process in accordance with the invention arein each case a Wittig reaction which is well-known, especially incarotenoid chemistry. In both cases similar reaction conditions can beused, with in general more drastic conditions, inter alia highertemperatures, being possible for the final process step. The tworeactants are each conveniently reacted with one another in a protic oraprotic polar organic solvent in the presence of a base. As suchsolvents there come into consideration especially lower aliphaticalcohols, for example, methanol and ethanol; lower halogenated aliphatichydrocarbons, for example, methylene chloride and chloroform; alicyclicethers, for example, epoxybutane and other oxiranes, andtetrahydrofuran; dimethylformamide; and dimethyl sulphoxide.

The reaction is effected in the first case (X+XI→XII) conveniently attemperatures in the range of about 0° C. to about 60° C., preferably atroom temperature, and in the second case (XII+XIII→II) conveniently attemperatures in the range of about 0° C. to about 60° C., preferably atabout 40° C. Moreover, it is advisable to use the respective phosphoniumsalt (X) or (XIII) in a slight excess, suitably in up to about 10percent excess. The working up is conveniently effected by partitioningthe mixture obtained after the reaction between water and an aprotic,polar organic solvent, such as a lower aliphatic ether, ester orhalogenated hydrocarbon, for example, diethyl ether, ethyl acetate or,respectively, methylene chloride or chloroform, separating the organicphase, washing this with saturated sodium chloride solution, extractingthe aqueous phase with further organic solvent, drying the combinedorganic phases, for example with anhydrous sodium sulphate or magnesiumsulphate, evaporating the organic phase, which is dried and freed fromdrying agent, and purifying the thus-obtained solid, for example, bycolumn chromatography and/or recrystallization.

After column chromatography, the compounds XII and II are normally eachobtained as an E/Z isomer mixture from which the (all E)-isomer can beisolated by recrystallization, for example, from hexane. In general, theisomerism of the respective product obtained can, if desired, becontrolled in the overall multi-stage process. Thus, starting from(4R)-α-terpinyl acetate of formula III ((4R)-III) there can be producedin sequence (1RS,2RS,4R)-IV, (3R)-V, (1R,2S,3R)-VI, (1R,2S,3R)-VII,(1'R,2'S,3'R)-VIII, (1'R,2'S,3'R,3RS)-IX, (1'R,2'S,3'R)-X,(1'R,2'S,3'R)-XII and (all-E,2R,5R,6S)-II. The corresponding enantiomerscan be produced from (4S)-α-terpinyl acetate.

A variant of the process in accordance with the present inventiondescribed above comprises converting the cyclopentylbutenone (VIII) intothe phosphonium salt (X) not via the pentadianol (IX), but converting itinto the same phosphonium salt (X) via two alternative intermediates;this variant involves three process steps and comprises the steps ofsubjecting the cyclopentylbutenone (VIII) to a Horner-Emmons olefinationwith a trialkyl phosphonoacetate in the presence of a base to form thecorresponding alkyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-2,4-dienoatehaving the formula ##STR28##

wherein Alkyl is C₁₋₆ -alkyl, (pentadienoic acid ester (XIV)), reducingthe pentadienoic acid ester (XIV) with deprotection of the silylatedhydroxy group to form5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dien-1-olhaving the formula ##STR29## (pentadienol (XV)), and converting thepentadienol (XV) into the(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt of formula X given above [phosphonium salt (X)]. The remainder ofthe multi-stage process for making 2,6-cyclolycopene-1,5-diol, that is,process steps X+XI→XII and XII+XIII→II, is effected as defined anddescribed above. The thus-modified process for making the lycopenemetabolite 2,6-cyclolycopene-1,5-diol of formula II starting froma-terpinyl acetate represents a further aspect of the present invention,as do the novel intermediates of formulae XIV and XV produced in thevariant as well as the individual processes steps VIII→XIV, XIV→XV andXV→X, that is, the one-stage processes defined above for the productionof the novel intermediates.

The reaction of the cyclopentylbutenone (VIII) with the trialkylphosphonoacetate (Homer-Emmons olefination) is conveniently effected ina lower aliphatic ether or diether for example, dimethoxyethane, as thesolvent and in the presence of a strong base, especially an alkali metalhydride, for example, sodium hydride; an alkali metal alkoxide, forexample, sodium methoxide or ethoxide; an alkyllithium, for example,butyllithium; or a lithium dialkylamide, for example, lithiumdiisopropylamide. The reaction is effected at low temperatures, namelyat temperatures below about -10° C.; the lower limit lies at about -60°C. It has been found to be practical to add a cooled solution of thetrialkyl phosphonoacetate slowly to a likewise cooled suspension of thestrong base in the same solvent while stirring and cooling and, after aperiod of stirring, also to add a solution of the cyclopentylbutenone(VIII) in the same solvent, with the temperature of the respectivemixture always being held below about -10° C. Moreover, it isrecommended to carry out these operations under an inert gas, forexample, nitrogen or argon. Finally, the reaction mixture is stirred forseveral hours, for example 5 to 15 hours, and gradually left to warm toroom temperature. The isolation and purification of the thus-obtainedpentadienoic acid ester (XIV) can be carried out analogously to theprocedure described in connection with process step VII→VIII, althoughafter the treatment with saturated aqueous ammonium chloride solutionand prior to the separation of the organic phase an additional organicsolvent for example, ethyl acetate, is suitably added for extraction.

The subsequent step of this process variant comprises the reduction ofthe ester group --COOAlkyl of the pentadienoic acid ester (XIV) as wellas the deprotection of the likewise present trimethylsilyloxy group. Thereduction is conveniently carried out using a reducing agentconventionally employed for this purpose, especially a metal hydride,for example, diisobutyl aluminium hydride or lithium aluminium hydride,or an alkoxy- metal hydride. Moreover, the reaction is convenientlyeffected in an aliphatic hydrocarbon, for example, hexane; an aliphaticor cyclic ether, for example, diethyl ether or tetrahydrofuran, a loweraliphatic alcohol, for example, ethanol, or another water-solubleorganic solvent at temperatures which are generally low. Whendiisobutylaluminium hydride is used as the reducing agent, the reactionis effected, for example, at temperatures which do not exceed a maximumof about -40° C. and which as a rule lie at about -60° C. Aftertreatment of the pentadienoic acid ester (XIV) with the reducing agent,the reaction mixture can, however, be left to warm to room temperature,and subsequently the work up can also be carried out analogously to theprocedure described in connection with the above described process stepVII→VIII with an included extraction step using, for example, ethylacetate as the extracting agent, whereby in comparison to the work upaccording to the foregoing process step VIII→XIV the evaporated organicphase is also treated with an organic or inorganic acid as an aqueoussolution, for example, hydrochloric acid (which brings about thedeprotection). This acid treatment is then conveniently followed by apartition of the mixture between water and the extracting agent, dryingand evaporation of the (combined) organic phase(s) and, if desired, alsofurther purification, for example, by recrystallization and/or columnchromatography.

The subsequent phosphonium salt formation XV→X can be carried outanalogously to the phosphonium salt formation IX→X described above, thatis, the equivalent reaction conditions apply to this reaction.

As mentioned above, the present invention is also concerned with novelintermediates produced in the manufacturing process (in both variants),that is,

3-(1-acetoxy-1-methylethyl)-6-oxo-heptanal of formula V,

3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol of formulaVI,

3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentaneof formula VII,

4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-oneof formula VIII,

5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-olof formula IX,

(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt of formula ##STR30##

wherein Ph is phenyl and X¹⁻⁻ is halide or hydrogen sulphate,2,7,11-trimethyl- 13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenal offormula XII,

alkyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-2,4-dienoatesof formula ##STR31##

wherein Alkyl is C₁₋₆ -alkyl,

as well as

5-[2-hydroxy-5-(1-hydroxy- 1 -methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dien-1-ol of formula XV,

in each case as the racemate or in the respective optically active formgiven above, which can be produced starting from (4R)- or (4S)α-terpinylacetate.

The present invention is illustrated by the following Examples:

EXAMPLE 1 Oxidative dihydroxylation III→IV

A solution of 50 g (255 mmol) of α-terpinyl acetate in 800 ml oftetrahydrofuran was cooled to 0° C. A solution of 50 g (316 mmol) ofpotassium permanganate in 1 l of water was added dropwise within 2 hourswhile stirring vigorously and, after removal of the cooling, thereaction mixture was stirred for a further hour. Then, the mixture wasfiltered through Celite® (filter aid consisting of kieselguhr (amorphoussilica or diatomaceous earth) of various particle sizes) and thefiltrate was extracted with ethyl acetate. The organic phase was driedover anhydrous magnesium sulphate and subsequently evaporated underreduced pressure. The residue was recrystallized from the minimum amountof ethyl acetate and added hexane at 4° C. and, in order to obtainadditional product, the mother liquor was purified by columnchromatography using silica gel and a hexane/ethyl acetate mixture (1:1)and the residue obtained therefrom by evaporation was recrystallized inthe same manner. The total yield of thus-obtained4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol, m.p. 88° C.,as white needles was 33.77 g (148 mmol; 65% of the theoretical yield;5.38 g of educt were recovered).

¹ H-NMR (300 MHz, CDCl₃): 3.36 [dd, J=1 1.4;4.4, H-C(2)]; 2.3 [br.s., 2xOH]; 2.01 [m, H-C(4)]; 1.94 [s, CH₃ COO]; 1.81 [dm, J=11.4, H-C(S)];1.67 [dm, J=11.4, H-C(3)]; 1.40 [m, H₂ -C(6)]; 1.39 [s, H₃ C(9)]; 1.38[s, H₃ C(10)]; 1.36 [m, H-C(3)]; 1.28 [m, H-C(5)]; 1.23 [H₃ C(7)].

¹³ C-NMR (75.5 MHz, CDCl₃): 170.57 [C=O]; 84.55 [C(8)]; 75.13 [C(2)];70.71 [C(1)]; 44.35 [C(4)]; 37.03 [C(5)]; 31.27 [C(3)]; 27.07 [C(7)];23.58 [C(9)]; 23.34 [C(10)]; 22.45 [CH₃ COO]; 21.68 [C(6)].

IR (CHCl₃): 3620 w, 3570 w, 3000 m, 2930 m, 1715 s, 1420 w, 1365 s, 1270s, 1150 m, 1115 m, 1035 m, 1010 m.

MS (EI, 70 eV, 250° C.): 215 (1, M+/-15), 197 (3), 187 (3), 170 (62),152 (50), 137 (43), 126 (100), 111 (73), 108 (84), 93 (48), 71 (55), 59(24), 43 (58).

Starting from optically active (R)-α-terpinyl acetate there is obtainedin the above manner the cyclohexanediol (IV) as a 1RS, 2RS,4R-diastereomer mixture; [α]_(D) ²³ :-3.3° (c=0.04 in CH₃ OH).

EXAMPLE 2 Oxidative cleavage IV→V

33.77 g (148 mmol) of4-(1-acetoxy-1-methylethyl)-1-methylcyclohexane-1,2-diol and 34.88 g(327 mmol) of anhydrous, finely mortared sodium carbonate were placed in1 l of methylene chloride and the mixture was cooled to 0° C. Then, 93.3g of an 85:15 mixture of lead(IV) acetate (156 mmol) and acetic acidwere added portionwise to the mixture in such a manner that thetemperature did not rise above 6° C. The mixture was stirred for onehour, treated with 50 ml of water and warmed to room temperature.Subsequently, the aqueous-organic mixture was filtered through Celite®,the organic phase was separated from the filtrate, the aqueous phase wasextracted with methylene chloride, the combined organic phases weredried over anhydrous magnesium sulphate, the dried organic phase wasevaporated under reduced pressure and the residue was purified by columnchromatography using silica gel as the stationary phase and a 3:2mixture of hexane and ethyl acetate as the eluting agent.

In this manner there were obtained 30.14 g (133 mmol) of3-(1-acetoxy-1-methylethyl)-6-oxo-heptanal as a white wax, m.p. 24° C.;the yield was 90% of theory.

¹ H-NMR (300 MHz, CDCl₃): 9.72 [dd, J=2.5;1,8, H-C(1)]; 2.58 [ddd,J=16.9;5.8;2.5, H-C(2)]; 2.46 [m, H₂ -C(5)]; 2.44 [m, H-C(3)]; 2.26[ddd, J=16.9;5.8;1.8, H-C(2)]; 2.13 [s, H₃ C(7)]; 1.93 [s, CH₃ COO];1.84 [m, H-C(4)]; 1.53 [s, H₃ C(2')]; 1.42 [s, H₃ C--C(1')]; 1.37 [m,H-C(4)].

¹³ C-NMR (75.5 MHz, CDCl₃): 207.89 [C(6)]; 201.62 [C(1)]; 170.12 [C═O];84.40 [C(1')]; 44.96 [C(2)]; 41.99 [C(5)]; 41.88 [C(3)]; 30.04 [C(7)];24.17 [C(4)]; 24.15 [C(2')]; 22.39 [CH₃ COO]; 22.02 [CH₃ --C(1')].

IR (CHCl₃): 3020 m, 2810 w, 2720 w, 1720 s, 1370 s, 1260 s, 1135 m, 1015m. MS (El, 70eV, 150° C.): 228 (1,M⁺); 169 (23); 154 (40); 122 (47); 110(100); 101 (32); 95 (41); 81 (89), 70 (38); 59 (35); 43 (95).

Starting from the 1RS,2RS,4R-diasteroisomer mixture of thecyclohexanediol (IV) there is obtained in the above manner theketoaldehyde (V) as the 3R-isomer, [α]_(D) ²³ :-6.3° (c=0.28 in CH₃ OH).

EXAMPLE 3 Intramolecular aldol condensation V→VI

11.59 g (51.1 mmol) of 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanal weredissolved in 250 ml of tetrahydrofuran together with 2.3 ml ofpiperidine, 2.3 ml of acetic acid and 1.15 ml of water, and the solutionwas stirred at room temperature for 21.5 hours. The solution was thenwashed in sequence with 5% sodium carbonate solution, with 2Nhydrochloric acid and with saturated sodium chloride solution and theaqueous phases were each extracted with tert.butyl methyl ether. Thecombined organic phases were dried with anhydrous magnesium sulphate andevaporated under reduced pressure, and the residue was then purified bycolumn chromatography using silica gel as the stationary phase and a13:7 mixture of hexane and ethyl acetate as the eluting agent.

In this manner there were obtained 5.26 g (23.1 mmol) of3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol as acolourless oil. The yield was 45% of theory; as 4.76 g (20.9 mmol, 41%)of the educt used were recovered, the yield of product was 77% based onthe conversion.

¹ H-NMR (300 MHz, CDCl₃): 9.78 [d, J=3.3, HC═O]; 3.04 [td, J=9.9;6.2,H-C(3)]; 2.51 [dd, J=9.9;3.3, H-C(2)]; 2.15-1.96 [m, H-C(4)]; 1.92 [s,CH₃ COO]; 1.84-1.52 [m, H-C(4), H₂ -C(5)]; 1.48 [s, H₃ C(2')]; 1.46 [s,H₃ C--C(1)]; 1.45 [s, H₃ C--C(1')].

¹³ C-NMR (75.5 MHz, CDCl₃): 205.5 [HC=O]; 170.2 [O-C=O]; 83.6 [C(1)];83.0 [C(1')]; 61.7 [C(2)]; 50.4 [C(3)]; 41.7 [C(4)]; 27.4 [C(2')]; 25.0[CH₃ --C(1')]; 24.9 [C(5)]; 21.8 [CH₃ --C(1)], 22.2 [CH₃ COO].

IR (CHCl₃): 3610 w, 3000 m, 1720 s, 1460 w, 1375 m, 1270 s, 1215 s, 1130m, 1020 w.

MS (EI, 70eV, 240° C): 228 (1, M+); 168 (19); 153 (32); 123 (37); 110(92); 95 (42); 81 (87); 69 (29); 59 (30); 43 (100).

Starting from the 3R-isomer of the ketoaldehyde (V) there is obtained inthe above manner the cyclopentanol (VI) as the 1R,2S,3R-isomer, [α]_(D)²⁴ :-4.3° (c=0.38 in CH₃ OH).

EXAMPLE 4 Silylation VI→VII

620 mg (2.72 mmol) of3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol and 600 mg(7.5 mmol) of imidazole were dissolved in 10 ml of methylene chlorideand a solution of 0.45 ml (3.56 mmol) of trimethylchlorosilane in 5 mlof methylene chloride was sprayed into the solution at room temperature.The reaction mixture was stirred at this temperature under nitrogen for17 hours. For the working up, the mixture was filtered, the filtrate wasevaporated under reduced pressure and the residue was purified by columnchromatography using silica gel and a 17:3 mixture of hexane and ethylacetate.

In this manner there were obtained 490 mg (1.63 mmol; 60% of thetheoretical yield) of 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentane as a white wax.

¹ H-NMR (300 MHz, CDCl₃): 9.45 [d, J=5, HC=O]; 2.93 [td, J=9.3;6.9,H-C(3)]; 2.19 [dd, J=9.3;4.2, H-C(2)]; 1.95-1.85 [m, H-C(4)]; 1.77 [s,CH₃ COO]; 1.59-1.42 [m, H-C(4), H₂ -C(5)]; 1.33 [s, H₃ C(2')]; 1.32 [s,H₃ C--C(1)]; 1.30 [s, H₃ C--C(1')]; -0.02 [s, (CH₃)₃ Si].

¹³ C-NMR (75.5 MHz, CDCl₃): 205.1 (HC═O); 170.0 (O-C=O); 86.0 [C(1)];83.3 [C(1')]; 63.1 [C(2)]; 48.9 [C(3)]; 41.4 [C(4)]; 27.1 [C(2')]; 24.9[C(5)]; 24.6 [CH₃ --C(1')]; 22.0 [CH₃ --C(1)]; 21.8 [CH₃ COO]; 1.8[(CH₃)₃ Si).

IR (CHCl₃): 2990 m, 1725 s, 1460 w, 1380 m, 1265 s, 1215 s, 1140 m, 1045m.

MS (EI, 70eV, 150° C.): 240 (39); 225 (100); 197 (20); 143 (92); 133(36); 122 (65); 81 (47); 73 (51); 43 (41).

Starting from the 1R,2S,3R-isomer of the cyclopentanol (VI) there isobtained in the above manner the formylcyclopentane (VII) as theIR,2S,3R-isomer, [α]_(D) ²⁰ :-12° C. (c=0.076 in CH₃ OH).

EXAMPLE 5 C₃ -chain lengthening and saponification VII→VIII

275 μl (2 mmol) of diisopropylamine were placed in 8 ml oftetrahydrofuran and 1.25 ml of butyllithium (2 mmol, 1.6M in hexane)were sprayed in under nitrogen at 0° C. The mixture was stirred for 30minutes, cooled to -70° C. and 110 μl (1.5 mmol) of acetone in 1 ml oftetrahydrofuran was sprayed in. The resulting solution of lithiumdiisopropylamide was stirred for 15 minutes and thereafter 300 mg (1mmol) of 3-(1-acetoxy-1-methylethyl)-2-formyl- 1-methyl-1-trimethylsilyloxycyclopentane in 1.5 ml of tetrahydrofuran weresprayed in. The reaction mixture was warmed to 0° C. within 2 hours andsubsequently treated cautiously with 10 ml of saturated ammoniumchloride solution. The organic phase was separated, washed with waterand saturated sodium chloride solution, dried with anhydrous magnesiumsulphate and finally evaporated under reduced pressure. Purification ofthe residue was effected as usual by column chromatography using silicagel and a 3:1 mixture of hexane and ethyl acetate.

In this manner there were obtained 210 mg (0.7 mmol; 70% of thetheoretical yield) of 4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-oneas a colourless oil.

¹ H-NMR (300 MHz, CDCl₃): 6.83 [dd, J=16.2;9.6, H-C(4)]; 6.01 [d,J=16.2, H-C(3)]; 2.33 [td, J=9.9;5.9, H-C(3')]; 2.21 [s, H₃ C(1)]; 2.16[t, J=9.6, H-C(2')]; 1.98 [m, H-C(4'α)]; 1.83 [m, H-C(5'α)]; 1.61 [m,H-C(4'β), H-C(5'β)]; 1.25 [s, H₃ C(2")]; 1.16 [s, H₃ C-(1')]; 1.14 [s,H₃ C--C(1")]; 0.08 [(H₃ C)3Si].

¹³ C-NMR (75.5 MHz, CDCl₃): 198.7 [C(2)]; 152.5 [C(4)]; 132.3 [C(3)];85.8 [C(1')]; 72.9 [C(1")]; 56.9 [C(2')]; 54.4 [C(3')]; 40.7 [C(5')];28.5 [C(2")]; 27.8 [CH₃ --C(1')]; 26.2 [C(1)]; 26.0 [CH₃ --C(1")]; 25.4[C(4')]; 2.2 [(CH₃)3 Si].

IR (CHCl₃): 3440 w, 2980 s, 2375 w, 1730 w, 1675 s, 1620 m, 1385 m, 1255s, 1050 m,860s.

MS (EI, 70 eV, 150° C.): 298 (2, M⁺); 280 (25); 265 (16); 240 (3 1); 227(28); 208 (42); 193 (29); 182 (30); 143 (100); 101 (62); 73 (50); 59(54); 43 (56).

Starting from the 1R,2S,3R-isomer of the formylcyclopentane (VII) thereis obtained in the above manner the cyclopentylbutenone (VIII) as the1'R,2'S, 3'R-isomer, [α]_(D) ²² :-116° (c=0.324 in CH₃ OH).

EXAMPLE 6 Grignard reaction VIII→IX

6.6 ml (6.6 mmol) of a 1M solution of vinylmagnesium bromide in diethylether were dissolved in 30 ml of tetrahydrofuran and the solution wasthen cooled to -50° C. under nitrogen. Subsequently, a solution of 490mg (1.64 mmol) of 4-[5-(1- hydroxy--methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-one in10 ml of tetrahydrofuran was slowly sprayed in, the reaction mixture wasstirred for 30 minutes, a further 3 ml of the ethereal solution ofvinylmagnesium bromide (3 mmol CH₂ ═CHMgBr) were added and the mixturewas warmed to 0° C.

For the working up, the mixture was treated with 20 ml of saturatedammonium chloride solution, the organic phase was separated, washed withsodium chloride solution, dried with anhydrous magnesium sulphate andevaporated under reduced pressure. Purification of the residue waseffected as usual by column chromatography using silica gel and a 17:8mixture of hexane and ethyl acetate.

In this manner there were obtained 190 mg (0.58 mmol, 35% of thetheoretical yield) of5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-olas a colourless oil.

¹ H-NMR (300 MHz, CDCl₃): 5.91 [dd, J=17.3;10.7, H-C(2)]; 5.65 [dd,J=15.8;8.8, H-C(5)]; 5.53 [d, J=15.8; H-C(4)]; 5.18 [dd, J=17.3;1.1,H-C(1)]; 4.98 [dd, J=10.7;1.1, H-C(1)]; 2.96 [br.s, 2 OH]; 2.19 [m,H-C(3')]; 1.90 [m, H-C(2')]; 1.81 [m, H-C(4'α)]; 1.73 [m, H-C(5'α)];1.49 [m, H-C(5'β)]; 1.38 [m, H-C(4'β)]; 1.34 [s, H₃ C--C(3)]; 1.17 [s,H₃ C--C(1')]; 1.10 [s, H₃ C(2"), H₃ C--C(1")]; 0.08 [s, (H₃ C)3-Si].

¹³ C-NMR (75.5 MHz, CDCl₃): 144.3 [C(2)]; 137.5 [C(4)]; 131.3 [C(5)];112.0 [C(3)]; 111.7 [C(1)]; 84.6 [C(1')]; 73.0 [C(1")]; 56.5 [C(2')];53.8 [C(3')]; 40.2 [C(5')]; 28.5 [C(2")]; 27.5 [Me-C(3)]; 26.6[Me-C(1")]; 25.8 [Me-C(1')]; 25.1 [C(4')]; 2.2 [(CH₃)3Si].

IR (NaCl): 3400 s, 3040 w, 2970 s, 1620 w, 1455 m, 1380s, 1245 s, 1095s, 1040 s, 835 s.

MS (EI, 70 eV, 80° C.): 326 (1, M⁺); 308 (28); 293 (13); 241 (40); 223(89); 218 (72); 197 (37); 173 (81); 143 (100); 117 (28); 73 (53); 57(23); 43 (44).

Starting from the 1'R,2'S,3'R-isomer of theyclopentylbutenone (VIII)there is obtained in the above manner the pentadienol (IX) as a1'R,2'S,3'R,3RS-isomer mixture, [α]_(D) ²⁵ :-85° (c=0.355 in CH₃ OH).

EXAMPLE 7 Deprotection and phosphonium salt formation IX→X

520 mg (1.6 mmol) of5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-oland 600 mg (1.75 mmol) of triphenylphosphonium bromide were dissolved in16 ml of a 1:1 mixture of methanol and chloroform and the solution wasstirred for 23 hours at room temperature under nitrogen and with theexclusion of light. Thereafter, the mixture was evaporated and theresidue, dissolved in a small amount of methylene chloride, wasprecipitated in ice-cold tert.butyl methyl ether. After decanting offthe supernatant and filtration the collected precipitate was washed withtert.butyl methyl ether and dried under reduced pressure.

In this manner there were obtained 1.09 g of crude(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumbromide. This product was used without purification in the next step ofthe process X+XI→XII (Example 8).

IR (paraffin oil): 3330 w, 2980 s, 2850 s, 1475 m, 1380 m, 1205 w, 1095w, 1080 w.

MS (EI, 70eV, 400° C.): 463 (2); 277 (12); 262 (100); 183 (63); 153 (9);108 (22).

Starting from the 1'R,2'S,3'R,3RS-isomer mixture of the pentadienol (IX)there is obtained in the above manner the phosphonium salt (X;Ph=phenyl, X¹⁻⁻ =Br) as the 1'R,2'S,3'R-isomer, [α]_(D) ²⁰ :-18.8°(c=0.085 in CH₃ OH).

EXAMPLE 8 First Wittig reaction X+XI→XII

200 mg (maximum 0.36 mmol) of crude(5-[2-hydroxy-5-(1-hydroxy-1-methyl-ethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-diphenyl)triphenylphosphoniumbromide and 50 mg (0.3 mmol) of 2,7-dimethyl-2,4,6-octatriene-1,8-dialwere placed in 2 ml of methylene chloride and treated with 1.5 ml of 1Nsodium hydroxide solution. The reaction mixture was then stirred at roomtemperature for 90 minutes. For work up, the mixture was partitionedbetween methylene chloride and water, the aqueous phase was separatedand the organic phase was dried with anhydrous magnesium sulphate andevaporated under reduced pressure. The residue was purified by columnchromatography using silica gel and a 7:3 mixture of hexane and ethylacetate.

In this manner there were obtained 33 mg (86 μmol, at least 28% of thetheoretical yield) of 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenalin the form of a mixture of E/Z-isomers as an orange coloured powder.After recrystallization from hexane there were obtained 12 mg (31 μmol;at least 10% of the theoretical yield) of this product as the(all-E)-isomer.

¹ H-NMR (400 MHz, CDCl₃): 9.45 [s, H-C(12')]; 7.02 [dd, J=14.4;11.9,H-C(15)]; 6.95 [d, J=11.9, H-C(14')]; 6.75 [dd, J=15.0; 11.4, H-C(11)];6.69 [dd; J=14.4; 11.9, H-C(15')]; 6.37 [d, J=15.0,H-C(12)]; 6.30 [d,J=11.9, H-C(14)]; 6.24 [d, J=15.7;H-C(8)]; 6.16 [d, J=11.4; H-C(10)];5.81 [dd, J=15.7;8.9, H-C(7)]; 2.30 [ddd, J=19.7;10.0;6.9, H-C(2)]; 2.24[dd, J=10.0;8.9, H-C(6)]; 2.03 [s, H₃ C(20)]; 1.99 [m, H-C(3α)]; 1.96[s, H₃ C(19)]; 1.88 [s, H₃ C(20')]; 1.79 [ddd, J=12.3;8.4;3.8, H-C(4α)];1.68 [ddd; J=13.3;10.1;8.4, H-C(4β)]; 1.53 [dtd, J=16.1;6.9;3.8,H-C(3β), 2 OH]; 1.24 [s, H₃ C(18)]; 1.18 (s,H₃ C(17)]; 1.16 [s,H₃C(16)].

¹³ C-NMR (100.6 MHz, CDCl₃): 194.3 [C(12')]; 148.7 [C(14)]; 141.5[C(13)]; 137.7 [C(8)]; 137.6 [C(15)]; 137.03 [C(13')]; 136.99 [C(12)];136.8 [C(9)]; 131.1 [C(14)]; 130.95 [C(10),C(7)]; 127.5 [C(15')]; 127.3[C(1)]; 82.2 [C(5)]; 73.1 [C(1)]; 55.7 [C(6)]; 54.4 [C(2)]; 40.0 [C(4)];28.6 [C(17)]; 27.5 [C(16)]; 26.7 [C(18)]; 25.1 [C(3)]; 13.1 [C(19)];13.0 [C(20)]; 9.6 [C(20')].

IR (CHCl₃): 3680 w, 3620 m, 3460 w, 3015 s, 2980 s, 2415 m, 1670 m, 1605m, 1530 m, 1490 m, 1425 m, 1215 s, 1050 s, 930 m.

MS (EI, 70 eV, 270° C.): 384 (100, M⁺); 366 (87); 326 (38); 277 (12);222 (21); 197 (21); 183 (22); 157 (32); 145 (32); 131 (20); 119 (22);105 (23); 95 (24); 43 (22).

UV/Vis (CH₃ COOC₂ H₅): 410 nm.

Starting from the 1'R,2'S,3'R-isomer of the phosphonium salt (X;Ph=phenyl, X¹⁻⁻ =Br) there is obtained in the above manner thetridecahexaenal (XII) as the 1'R,2'S,3'R-isomer.

EXAMPLE 9 Second Wittig reaction XII+XIII→II

A solution of 59 mg (0.16 mmol) of 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenaland 94 mg (0.17 mmol) of(3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium bromidein 5 ml of methylene chloride was treated with 1 ml of 1N sodiumhydroxide solution and the reaction mixture was heated at the refluxtemperature for 90 minutes. For the working up, the solution wassubsequently partitioned between ethyl acetate and water, the aqueousphase was separated and the organic phase was washed with sodiumchloride solution, dried with anhydrous sodium sulphate and evaporatedunder reduced pressure. The residue was purified by columnchromatography using silica gel and a 2:1 mixture of hexane and ethylacetate.

In this manner there were obtained 38 mg (67 mmol; 43% of thetheoretical yield) of 2,6-cyclolycopene-1,5-diol in the form of amixture of (E/Z)-isomers as a red powder. For further purification, thiscan be recrystallized, for example, from hexane, which gives the(all-E)-isomer, m.p. 78° C. with decomposition.

¹ H-NMR (300 MHz, CDCl₃): 6.63 [dd, J=15,0; 11,1, H-C(11')]; 6.63 [dd,J=14.9;11.3, H-C(11)]; 6.63 [m, H-C(15), H-C(15')]; 6.51 [dd,J=15.1;1.0, H-C(7')]; 6.36 [d, J=14.9; H-C(12)]; 6.35 [d, J=15.0,H-C(12')]; 6.26 [d, J=15.1, H-C(8')]; 6.25 [d, J=15.7, H-C(8)]; 6.23 [m,H-C(14), H-C(14')]; 6.19 [d, J=11.1, H-C(I0')]; 6.16 [d, J=1 1.3,H-C(10)]; 5.94 [d, J=11.0, H-C(6')]; 5.73 [dd, J=15.7; 9.0, H-C(7)];5.16 [m, H-C(2')]; 2.30 [ddd, J=17.1;10.1;7.0, H-C(2)]; 2.23 [dd,J=10.1;9.0, H-C(6)]; 2.12 [m, H₂ -C(3'), H₂ -C(4')]; 1.98 [s, H₃ C(20),H₃ C(20')]; 1.97 [s, H₃ C(19)]; 1.95 [m, H-C(3α)]; 1.94 [s, H₃ C(19')];1.82 [s, H₃ C(18')]; 1.79 [ddd, J=12.3;8.4;3.8, H-C(4α)]; 1.68 [s, H₃C(16')]; 1,.67 [m, H-C(4β)]; 1.62 [s, H₃ C(17')]; 1.53 [m, H-C(3β)];1.24 [s, H₃ C(16)]; 1.19 [s, H₃ C(18)]; 1.18 [s, H₃ C(17)].

¹³ C-NMR (75,5 MHz, CDCl₃): 139.5 [C(5')]; 138.2 [C(8)]; 138.0 [C(12)];137.3 [C(12')]; 136.7 [C(13')]; 136.3 [C(9')]; 136.2 [C(13)]; 135.4[C(8')]; 134.9 [C(9)]; 132.9 [C(14)]; 132.5 [C(14')]; 131.8 [C(1')];131.6 [C(10')]; 131.5 [C(10)]; 130.3 [C(15)]; 129.9 [C(15')]; 129.4[C(7)]; 125.7 [C(6')]; 125.2 [C(11')]; 124.8 [C(7')]; 124.6 [C(11)];123.9 [C(2')]; 82.2 [C(5)]; 73.1 [C(1)]; 55.6 [C(6)]; 54.3 [C(2)]; 40.2[C(4')]; 39.7 [C(4)]; 28.5 [C(16)); 27.4 [C(17)]; 26.7 [C(3')+C(18)];25.7 [C(16')]; 25,1 [C(3)]; 17.7 [C(17')]; 17.0 [C(18')]; 13.1 [C(19)];12.9 [C(19')]; 12.8 [C(20)+C(20')].

IR (CHCl₃): 3640 w, 3600 m, 3440 w, 3010 s, 2980 s, 2860 m, 2390 m, 1515m, 1470 w, 1415 m, 1220 s, 1045 s.

MS (EI, 70eV, 300° C.): 570 (52, M+); 552 (2); 478 (14); 464 (12); 223(19); 209 (25); 159 (52); 145 (62); 133 (36); 105 (62); 91(43); 69 (31);55 (20); 43 (100).

UV/V is (CH₃ COOC₂ H₅): 491, 459, 433 nm; (petroleum ether): 487, 455,429 nm.

Starting from the 1'R,2'S,3'R-isomer of tridecahexaenal (XII) there isobtained in the above manner 2,6-cyclolycopene-1,5-diol (II) as theall-E,2R,5R,6S-isomer having the following circular dichroism data (CD):

CD (diethyl ether:isopentane: ethanol 5:5:2, -180° C.): 216.5 (-3.8,neg. max), 228 (+1.7, pos. max), 244 (+0.2, pos. max), 283.5 (+0.6, pos.max), 297.5 (+3.0, pos. max), 443.5 (-4.9, neg. max), 455 (-3.6, pos.max), 469 (-7.2, neg. max), 498 (-3.4, pos. max), 504 (-8.5, neg. max),515.5 (-1.4, pos. max).

EXAMPLE 10 Olefination VIII→XIV

900 mg of an about 55% oily suspension sodium hydride (about 20 mmol) inpetroleum were placed in 30 ml of dimethoxymethane under argon and themixture was cooled to --30° C. Then a solution of 4.5 ml (22.5 mmol) oftriethyl phosphonoacetate in 5.5 ml of dimethoxyethane was sprayed in insuch a manner that the temperature always remained below -20° C. Themixture was stirred at -25° C. to -20° C. for 45 minutes and thereaftera solution of 2 g (6.67 mmol) of4-(5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-one(prepared as described in Example in 5) in 3 ml of dimethoxyethane wassprayed in in such a manner that the temperature remained below -15° C.The solution was stirred for about 16 hours, during which it warmed toroom temperature. For work up, 10 ml of saturated ammonium chloridesolution were cautiously added to the solution and the separated aqueousphase was extracted three times with ethyl acetate, and the combinedorganic phases were washed with saturated sodium chloride solution,dried over anhydrous magnesium sulphate and evaporated under reducedpressure. Purification of the residue was effected by flashchromatography using silica gel and a mixture of 15-40% ethyl acetate inhexane.

In this manner there were obtained 1.19 g [48% of the theoretical yield;98% yield based on reacted cyclopentylbutanone (VIII), as 1.03 g ofunreacted starting material remained] of ethyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-2,4-dienoate.The product was obtained as a colourless oil and consisted of acis-trans isomer mixture of the pentadienoic acid ester (XIV).

¹ H-NMR (300 MHz, CDCl₃): 7.55 [d,J=6.1,H-C(4)cis]; 6.16 [m,H-C(4)trans,H-C(5)]; 5.71 [s,H-C(2)trans]; 5.62 [s,H-C(2)cis]; 4.13 [m,H₂ -C(1'"))];2.31 [m,H-C(3')]; 2.29 [s,CH₃ -C(3)trans]; 2.12 [m,H-C(2')]; 2.00 [s,CH₃ --C(3)cis]; 1.96 [m,H-C(4')]; 1.80 [m,H-C(5')]; 1.55 [m,H-C(4'),H-C(5')]; 1.27 [t,J=6.2, Me(2'")'; 1.24, 1.22, 1.18, 1.16, 1.15, 1.14[6s, CH--C(1'), CH₃ --C(1"), CH₃ (2")].

¹³ C-NMR (75.5 MHz, CDCl₃): 167.3/166.4 [C(1)]; 152.4/151,1 [C(3)];141.8/140.4 [C(5)]; 134.6/128.9 [C(4)]; 117.9/115.9 [C(2)]; 85.5/85.4[C(1')]; 73.3/73.2 [C(1")]; 59.6/59.5 [C(1'")]; 57.7/57.4 [C(2')];54.6/54.3 [C(3')]; 40.5 [C(5')]; 28.3/28.2 [C(2')]; 27.7/27.2 [CH₃--C(1')]; 26.1/25.9 [CH₃ --C(1")]; 25.4/25.2 [C(4')]; 21.2 [CH₃ --C(3)];14,3/13,8 [C(2'")].

IR (CHCl₃): 3550w, 2965s, 2875m, 2455w, 1690s, 1630s, 1610s, 1450m,1375s, 1350m, 1250s, 1150s, 1090s, 1040s, 1015m, 1000m, 975m, 940m. MS(EI, 70 eV, 150° C.): 368 (M⁺, 98); 353 (12); 335 (11); 309 (98), 278(21), 263 (21); 232 (15); 174 (20); 143 (100); 73 (34).

EXAMPLE 11 Reduction and deprotection XIV→XV

200 mg (0.54 mmol) of ethyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-2,4-dienoatein 3 ml of hexane were cooled to -65° C. under argon and 4 ml of a 1Msolution of diisobutyl aluminium hydride were sprayed in such a mannerthat the temperature of the reaction mixture did not rise above -60° C.The solution was warmed to room temperature within an hour. Then 3 ml ofsaturated ammonium chloride solution were sprayed in cautiously, theseparated aqueous phase was extracted three times with ethyl acetate andthe combined organic phases were evaporated, dissolved in 6 ml oftetrahyrofuran and treated with 0.5 ml of 2M hydrochloric acid. Theresulting solution was stirred for 30 minutes and partitioned betweenethyl acetate and water, and the separated aqueous phase was extractedthree times with ethyl acetate. The combined organic phases were driedover anhydrous magnesium sulphate and evaporated, and the residue wassubjected to flash column chromatography using silica gel and a mixtureof 30-100% ethyl acetate in hexane.

In this manner there were obtained 20 mg (14.5% of the theoreticalyield) of 20 5-[2-hydroxy-5-(I -hydroxy- 1-methylethyl)-2-methyl-cyclopentyl 1-3-methyl-penta-2,4-dien-1-ol as awhite solid.

¹ H-NMR (300 MHz, dimethyl sulphoxide): 6.27 [d,J=15.8,H-C(4)]; 5.94[d,J=15.8,H-C(4)]; 5.67 [dd,J=15.6; 8.4,H-C(5)]; 5.60 [dd,J=15.8;8.6,H-C(5)]; 5.43 (t,J=6.6,H-C(2)]; 5.30 (t,J=6.6,H-C(2)]; 4.53[t,J=6.6,OH]; 4.05 [m,H₂ -C(1)]; 3.88 [t,J=6.6;OH]; 3.33 [s,OH]; 2.03[m,H-C(2'),H-C(3')]; 1.76 [s,CH₃ --C(3)]; 1.75 [m,H-C(5')]; 1.68 [s,CH₃-C(3)]; 1.56 [m,H-C(4), H-C(5')]; 1.44 [m,H-C(4')];1.06/1.05/1.01/0.98/0.97 [5s,CH₃ -C(1'),CH₃ --C(1"),CH₃ (2")].

¹³ C-NMR (75.5 MHz, dimethyl sulphoxide): 135.1/132.2 [C(5)];134.7/127.3 [C(4)]; 129.9/128.4 [C(2)]; 57.7/56.9 [C(1)]; 55.6/55.4[C(2')]; 53.9/53.8 [C(3')]; 40.4/40.3 [C(5')]; 29.9/29.8127.8/27.6126.2[CH₃ --C(1'),CH₃ --C(1"),C(2")]; 24.5 [C(4')]; 20.6/12.6 [CH₃ --C(3)].

IR (CHCl₃): 3685m, 3610m, 3420m, 3010s, 2970s, 2925m, 1605m, 1515w,1420m, 1380m, 1230s, 1050m, 1030m, 1010m, 975w, 930m. MS (EI, 70 eV,150° C.): 236 (M⁺ 18.18); 218 (14); 203 (12); 178 (61), 160 (25),145(25); 120 (100); 105 (39); 93 (22); 59 (18); 43 (24).

EXAMPLE 12 Phosphonium salt formation XV→X

20 mg (0.078 mmol) of5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methylcyclopentyl]-3-methyl-penta-2,4-dien-1-oland 30 mg (0.086 mmol) of triphenylphosphonium bromide were dissolved in2 ml of methanol and the solution was stirred at room temperature for 29hours under nitrogen and with the exclusion of light. Thereafter, thereaction mixture was introduced into about 100 ml of ice-cold tert.butylmethyl ether and the phosphonium salt produced in this mannerprecipitated. After decantation of the supernatant and filtration thecollected precipitate was washed with tert.butyl methyl ether and driedunder reduced pressure.

In this manner there were obtained 29.3 mg (65% of the theoreticalyield) of (5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphonium bromide as a white solid. This product can beconverted into 2.6-cyclolycopene-1,5-diol in accordance with Examples 8and 9.

We claim:
 1. A process for making a compound having the formula##STR32## comprising the steps of (a) oxidatively dihydroxylatingα-terpinyl acetate having the formula ##STR33## to form4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having theformula ##STR34## (cyclohexanediol (IV)), (b) oxidatively cleaving thecyclohexanediol (IV) to form 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanalhaving the formula ##STR35## (ketoaldehyde (V)), (c) subjecting theketoaldehyde (V) to an intramolecular aldol condensation to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having theformula ##STR36## (cyclopentanol (VI)), (d) silylating the cyclopentanol(VI) to form 3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentane having the formula ##STR37##(formylcyclopentane (VII)), (e) subjecting the formylcyclopentane (VII)to a C₃ -chain lengthening with acetone and simultaneously to asaponification for the cleavage of the acetyl group to form4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-onehaving the formula ##STR38## (cyclopentylbutenone (VIII)), (f) reactingthe cyclopentylbutanene (VIII) with vinylmagnesium bromide to form5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-1,4-dien-3-olhaving the formula ##STR39## (pentadienol (IX)), (g) converting thepentadienol (IX) with deprotection of the silylated hydroxy group toform(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt having the formula ##STR40## wherein Ph is phenyl and X¹⁻⁻ ishalide or hydrogen sulphate, (phosphonium salt (X)), (h) subjecting thephosphonium salt (X) to a Wittig reaction with2,7-dimethyl-2,4,6-octatriene-1,8-dial having the formula ##STR41## (C₁₀-dial (XI)) to form 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-trideca-2,4,6,8,10,12-hexaenal having the formula ##STR42## (tridecahexaenal (XII)), and (i)subjecting the tridecahexaenal (XII) to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt havingthe formula ##STR43## wherein Ph is phenyl and X²⁻⁻ is halide orhydrogen sulphate, (phosphonium salt (XIII)) to form the compound offormula II.
 2. The process of claim 1, wherein the α-terpinyl acetate offormula III is (4R)-α-terpinyl acetate.
 3. A process for making acompound having the formula ##STR44## comprising the steps of (a)oxidatively dihydroxylating a-terpinyl acetate having the formula##STR45## to form4-(1-acetoxy-1-methylethyl)-1-methyl-cyclohexane-1,2-diol having theformula ##STR46## (cyclohexanediol (IV)), (b) oxidatively cleaving thecyclohexanediol (IV) to form 3-(1-acetoxy-1-methylethyl)-6-oxo-heptanalhaving the formula ##STR47## (ketoaldehyde (V)), (c) subjecting theketoaldehyde (V) to an intramolecular aldol condensation to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-cyclopentanol having theformula ##STR48## (cyclopentanol (VI)), (d) silylating the cyclopentanol(VI) to form3-(1-acetoxy-1-methylethyl)-2-formyl-1-methyl-1-trimethylsilyloxy-cyclopentanehaving the formula ##STR49## (formylcyclopentane (VII)), (e) subjectingthe formylcyclopentane (VII) to a C₃ -chain lengthening with acetone andsimultaneously to a saponification for the cleavage of the acetyl groupto form4-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-buten-2-onehaving the formula ##STR50## (cyclopentylbutenone (VII)), (f) subjectingthe cyclopentylbutenone (VIII) to a Homer-Emmons olefination with atrialkyl phosphonoacetate in the presence of a base to form thecorresponding alkyl5-[5-(1-hydroxy-1-methylethyl)-2-methyl-2-trimethylsilyloxy-cyclopentyl]-3-methyl-penta-2,4-dienoatehaving the formula ##STR51## wherein Alkyl is C₁₋₆ -alkyl, (pentadienoicacid ester (XIV)), (g) reducing the pentadienoic acid ester (XIV) withdeprotection of the silylated hydroxy group to form5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dien-1-olhaving the formula ##STR52## (pentadienol (XV)), (h) converting thepentadienol (XV) into a(5-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]-3-methyl-penta-2,4-dienyl)triphenylphosphoniumsalt having the formula ##STR53## wherein Ph is phenyl and X¹⁻⁻ ishalide or hydrogen sulphate, (phosphonium salt (X)), (i) subjecting thephosphonium salt (X) to a Wittig reaction with2,7-dimethyl-2,4,6-octatriene-1,8-dial having the formula ##STR54## [C,₀-dial (XI)] to form 2,7,11-trimethyl-13-[2-hydroxy-5-(1-hydroxy-1-methylethyl)-2-methyl-cyclopentyl]trideca-2,4,6,8,10,12-hexaenalhaving the formula ##STR55## (tridecahexaenal (XII)), and (j) subjectingthe tridecahexaenal (XII) to a Wittig reaction with a (3,7,11-trimethyl-dodeca-2,4,6,10-tetraenyl)triphenylphosphonium salt havingthe formula ##STR56## wherein Ph is phenyl and X²⁻⁻ is halide orhydrogen sulphate, (phosphonium salt (XIII)) to form the compound offormula II.
 4. The process of claim 3, wherein the α-terpinyl acetate offormula III is (4R)-α-terpinyl acetate.